Raman spectroscopic method for the determination of medroxyprogesterone acetate in a pharmaceutical suspension: validation of quantifying abilities, uncertainty assessment and comparison with the high performance liquid chromatography reference method.

An alternative fast and non-destructive validated Raman spectroscopic analytical procedure, requiring no sample preparation, was compared with the industrially applied HPLC reference method (Pfizer Manufacturing Belgium) for the quantitative determination of medroxyprogesterone acetate (MPA) in DepoProvera suspensions (150 mg mL(-1), Pfizer). The Raman calibration model was developed by plotting the peak intensity of the baseline-corrected and normalized spectral band (corrected by external standard measurements) between 1595 and 1620 cm(-1) against known MPA concentrations in standards. At this band, no spectral interferences from the suspension medium are observed. The most suitable model for the calibration data (straight line or higher order polynomial) was determined by evaluating the fit and predictive properties of the models. In a second step, the developed Raman spectroscopic analytical method was validated by calculating the accuracy profile on the basis of the analysis results of validation samples. Furthermore, based on the data of the accuracy profile, the measurement uncertainty was determined. Finally, as the aim of the alternative method is to replace the destructive, time-consuming HPLC method, requiring sample preparation, it needs to be demonstrated that the new Raman method performs at least as good as the HPLC method. Therefore, the performance (precision and bias) of both methods was compared. A second order polynomial calibration curve through the calibration data supplies the best predictive properties and gives an acceptable fit. From the accuracy profile, it was concluded that at the target concentration (150 mg mL(-1)), 95 out 100 future routine measurements will be included within the acceptance limits (5%). Comparison of the alternative method with the reference method at the target concentration indicates that the Raman method performs at least as good as the HPLC method for precision (repeatability and intermediate precision) and bias. The fast and non-destructive Raman method hence provides an alternative for the destructive and time-consuming HPLC procedure.

Tablets prepared by single-step granulation/tabletting: interparticulate binding mechanism and stability.

The binding mechanism of tablets prepared by single-step granulation/tabletting (SSGT), a novel technique for the production of tablets, was evaluated. SSGT yielded hard tablets having a short disintegration time due to their porous, spongelike internal structure. Calculation of the interaction factor and electrical conductance tests confirmed the presence of solid bridges that provided a higher tensile strength to these compacts in comparison to tablets prepared by conventional tabletting techniques. At high relative humidity, moisture sorption and glass-to-rubber transition of the binder (polyvinylpyrrolidone), or condensation of moisture on the internal pore surface, reduced the tensile strength of the SSGT-manufactured tablets. Contrary to tablets prepared by granulation and compression, the SSGT tablets did not harden during storage under conditions of varying relative humidity (alternating the relative humidity every 24 hr between 33% and 75%).

Development of an enteric-coated pellet formulation of F4 fimbriae for oral vaccination of suckling piglets against enterotoxigenic Escherichia coli infections.

A multi-particulate formulation of F4 fimbriae was developed for oral vaccination of suckling piglets against enterotoxigenic Escherichia coli infections. A feasibility test showed that incorporation of F4 fimbriae in a disintegrating pellet formulation consisting of 87.5% Pharmatose 200 M, 2.5% Avicel CL 611 and 10% Explotab by extrusion/spheronisation and subsequent fluid bed drying resulted in the maintenance of 69+/-12% of the biological activity. But subsequent coating resulted in pellets with poor enteric properties, although good in vivo immunising results were obtained after administration to piglets. From the economical point of view, a pellet formulation was optimised to decrease vaccine dose and dosing frequency. After disintegration testing, pellets consisting of lactose (alpha-lactose monohydrate 90 mesh/beta-lactose 75/25 (w/w)) and microcrystalline cellulose in a ratio of 80/20 (w/w) showed a sponge-like structure from which F4 fimbriae could be released. Coating of these pellets resulted in good enteric properties. To improve disintegrating properties of the pellets, the lactose concentration was increased or sodium carboxymethyl starch was added. But this resulted in poor enteric properties after coating. Dissolution test showed that F4 fimbriae were released from the optimised enteric-coated pellets but interaction between F4 fimbriae and the coating polymer was seen. This incompatibility leads to unpredictable in vitro quantification of F4 biological activity.

Effect of different sterilisation methods on the properties of bioadhesive powders and ocular minitablets, and clinical evaluation.

The purpose of this study was to evaluate the influence of gamma-irradiation and dry heat sterilisation on the properties of a bioadhesive powder mixture containing ciprofloxacin and its corresponding ocular minitablets. The molecular weight characteristics of drum dried waxy maize starch (DDWM), employed as major component of the bioadhesive formulation, the decay kinetics of radicals, the rheological properties of the bioadhesive polymers and the microbial activity of ciprofloxacin were studied. The influence of the different sterilisation methods on the characteristics of the ocular minitablets was investigated by measuring the crushing strength, the friability, and the in vitro release of ciprofloxacin from the minitablets. Finally, the clinical value of the selected sterilised minitablets was evaluated in seven healthy volunteers. Both sterilisation methods similarly affected the properties of the bioadhesive formulation by inducing stable radicals and decreasing the molecular weight of DDWM, although no changes in the microbiological activity of ciprofloxacin were measured. An obvious influence of both sterilisation methods was observed in the in vitro release study. The crushing strength and friability of the minitablets were not significantly influenced by gamma-irradiation. Based on these data, gamma-irradiation was more adequate as sterilisation method for the bioadhesive ocular minitablets than dry heat sterilisation, because it affected the least the physical properties of the minitablets. Therefore, the gamma-sterilised minitablets were selected for an in vivo evaluation in seven volunteers. The concentration of ciprofloxacin in the tear film remained above its MIC value for the most common ocular pathogens for at least 8 h. Consequently, the gamma-irradiated minitablets containing ciprofloxacin can be considered as a promising formulation to treat bacterial keratitis and conjunctivitis.

Extrusion granulation and high shear granulation of different grades of lactose and highly dosed drugs: a comparative study.

Formulations containing different lactose grades, paracetamol, and cimetidine were granulated by extrusion granulation and high shear granulation. Granules were evaluated for yield, friability, and compressibility. Tablets were prepared from those granules and evaluated for tensile strength, friability, disintegration time, and dissolution. The different lactose grades had an important effect on the extrusion granulation process. Particle size and morphology affected powder feeding and power consumption, but had only a minor influence on the granule and tablet properties obtained by extrusion granulation. In contrast, the lactose grades had a major influence on the granule properties obtained by high shear granulation. Addition of polyvinylpyrrolidone (PVP) was required to process pure paracetamol and cimetidine by high shear granulation, whereas it was feasible to granulate these drugs without PVP by extrusion granulation. Granules prepared by extrusion granulation exhibited a higher yield and a lower friability than those produced by high shear granulation. Paracetamol and cimetidine tablets compressed from granules prepared by extrusion granulation showed a higher tensile strength, lower friability, and lower disintegration time than those prepared from granules produced by high shear granulation. Paracetamol tablets obtained via extrusion granulation exhibited faster dissolution than those obtained via high shear granulation. For all lactose grades studied, extrusion granulation resulted in superior granule and tablet properties in comparison with those obtained by high shear granulation. These results indicate that extrusion granulation is more efficient than high shear granulation.

Single-step granulation/tabletting of different grades of lactose: a comparison with high shear granulation and compression.

The influence of the particle size, particle morphology and crystallinity of lactose on the extrusion properties and on the quality of tablets were investigated using single-step granulation/tabletting as a tabletting technique. Results showed that particle size and type of lactose (alpha-lactose monohydrate, anhydrous beta-lactose and spray dried lactose) affected the powder feeding, the process performance as well as the process capacity. Different grades of lactose yielded tablets with similar tensile strength, but significantly different disintegration time. Single-step granulation/tabletting always yielded tablets with a significantly higher tensile strength and similar or significantly lower disintegration time compared to high shear granulation and compression. The tensile strength of alpha-lactose monohydrate tablets (without and with PVP) did not change during one year of storage at 60% RH-25 degrees C and at 75% RH-40 degrees C, whereas a significant increase in disintegration time was observed. It can be concluded that although the lactose grade affected the performance and the optimal parameters of single-step granulation/tabletting, all lactose grades can be efficiently processed using this technique.

Twin screw granulation as a simple and efficient tool for continuous wet granulation.

The modification of a twin screw extruder for continuous wet granulation was investigated. Modification of the extruder setup as well as the screw design allowed the continuous wet granulation of alpha-lactose monohydrate without the need of a wet sieving step. The robustness of twin screw granulation was evaluated by studying the influence of processing parameters and formulation variables on the process performance and on the properties of alpha-lactose monohydrate granules and tablets. The process reproducibility during long term production was evaluated. Screw speed (200-450 rpm) and total input rate (5.5-9.5 kg/h) had no significant influence on the granule properties, while the water concentration during granulation influenced the process as well as the granule properties. At a water concentration (calculated on wet granule basis) of 5.5-8.5%, continuous twin screw granulation of alpha-lactose monohydrate 200 M was feasible and the granules obtained had good properties. PVP addition mainly affected tablet properties. Tablets made from granules containing 2.5% PVP had a tensile strength above 0.94 MPa, a friability below 1% and a disintegration time ranging between 495 and 576 s. Tablets containing hydrochlorothiazide complied with the dissolution requirements as 60% was released after 5 and 15 min from tablets without PVP and with 2.5% PVP, respectively. No problems were observed during continuous twin screw granulation over a period of 8h and the granule and tablet properties were reproducible throughout the process. These results indicated that twin screw granulation is an efficient tool for continuous wet granulation.

Gastrointestinal transit time of nondisintegrating radio-opaque pellets in suckling and recently weaned piglets.

The objective was to determine the gastrointestinal (GI) transit times of pellets in piglets at different time points around weaning, as transit times are essential criteria to develop oral drug delivery systems. Nondisintegrating radio-opaque pellets were given orally in order to define the transit times by radiography. The radiographs were analysed with a software programme to calculate the number of pellets present in the different parts of the GI tract. In suckling piglets, the gastric emptying was faster (75% in 1.5 to 3.5 h), and the colonic accumulation (to 73%) was greater than in weaned piglets (3 days, 2 and 3 weeks postweaning, 65% gastric emptying in 18 h, 75% in 17 h, and 75% in 7 h, respectively; maximal colonic accumulations of 48%). Immediately after weaning, the transit was markedly prolonged but shortened with increased postweaning time (3 days, 2 and 3 weeks postweaning, 85% excretion in 175.5, 77, and 50.5 h, respectively). Three weeks postweaning, the transit was no longer affected by weaning as transit times were similar to values reported in growing and adult pigs, and retention appeared to be restricted to the stomach and the colon. These data are of crucial importance in the design of enteric-coated formulations for oral administration of vaccines and therapeutics to young piglets and for human research using the pig model.

Enteric-coated pellets of F4 fimbriae for oral vaccination of suckling piglets against enterotoxigenic Escherichia coli infections.

To prevent enterotoxigenic Escherichia coli (ETEC) induced postweaning diarrhoea, the piglet needs an active mucosal immunity at the moment of weaning. In the present study, the feasibility of oral vaccination of suckling piglets against F4+ETEC infection with F4 fimbriae was studied. Furthermore, oral vaccination with enteric-coated pellets of F4 fimbriae was compared to vaccination with F4 fimbriae in solution. Therefore, piglets were orally administered 1mg F4 fimbriae in pellets or in solution during three successive days at the age of 7 and 21 days, whereas control piglets were not vaccinated. Five days postweaning (33 days of age), all animals were orally challenged with F4+ETEC. Despite the induction of an immune response upon oral administration of both F4 fimbriae in pellets as in solution, the colonisation of the small intestine by F4+ETEC upon oral challenge could not be prevented. However, a marginal but significant reduction in F4+ E. coli faecal excretion was found in the piglets vaccinated with F4 fimbriae in pellets, indicating that the use of an enteric-coat which protects the F4 fimbriae against inactivation by milk factors and degradation by enzymes and bile improves vaccination.

Characterization and in vivo evaluation of ocular bioadhesive minitablets compressed at different forces.

The influence of the compression force on the physical properties, the in vitro release and the in vivo behavior of ocular minitablets is evaluated in the present study. The bioerodible minitablets (Ø 2 mm, 6 mg) were produced at different compression forces. The crushing strength, friability, water uptake, hydration and swelling of the minitablets both in vitro as well as in vivo after application in the cul-de-sac were evaluated. The friability remained below 1% only for the minitablets made at 0.500 and 0.750 kN. The crushing strength measured was 3.53+/-0.98, 12.34+/-1.69 and 18.64+/-2.37 N for minitablets made at 0.250, 0.500 and 0.750 kN, respectively. The full hydration time equalled 20 and 30 min for minitablets compressed at 0.250 kN and 0.500-0.750 kN, respectively. Increasing the compression force resulted in a decreased swelling capacity. The in vivo release was evaluated in healthy volunteers using a non-invasive method to measure the apparent sodium fluorescein concentration in the tearfilm-cornea compartment as a function of time. The longest residence time of the fluorescent tracer at the administration site was obtained by the minitablets compressed at 0.750 kN. The in vitro release was evaluated with three different dissolution methods: the reciprocating cylinder method, vials in an oscillatory shaking bath and a static method with vials. The best correlation with the in vivo behavior of the matrix minitablets was obtained with the shaking bath method.

Continuous twin screw extrusion for the wet granulation of lactose.

The suitability of continuous twin screw extrusion for the wet granulation of alpha-lactose monohydrate was studied and compared with conventional high shear granulation. The influence of process parameters (screw speed and total input rate) and formulation variables (water and polyvinylpyrrolidone (PVP) concentration) on the properties of granules (yield, particle size distribution, friability and compressibility) and tablets (tablet tensile strength, friability and disintegration time) was investigated. Variation of the formulation and process parameters had a major effect on the process feasibility. Optimization of these parameters is required to allow continuous processing and to ensure a high yield. Total input rate, screw speed and water concentration had a minor influence on the granule and the tablet properties. The addition of PVP had no major influence on the granule properties, but significantly affected the tablet characteristics. For granules formulated with and without PVP a yield above 50%, a friability below 30% and a compressibility below 15% was obtained. Tablets without PVP showed a tensile strength below 0.6 MPa, a friability above 1% and a disintegration time below 3 min, whereas tablets with PVP showed a tensile strength above 0.6 MPa, a friability below 1% and a disintegration time ranging from 8 to 15 min. High shear granulation was only possible when PVP was added and it required a higher amount of water. It was concluded that wet granulation of alpha-lactose monohydrate using continuous twin screw extrusion is a robust process and might offer a suitable alternative for high shear granulation in the pharmaceutical industry.

Evaluation of a mucoadhesive tablet for ocular use.

The present study investigates the use of a polymer mixture containing Carbopol 974P and drum dried waxy maize starch to obtain prolonged drug release to the anterior eye segment. Two dosage forms with this composition are compared: a hydrated polymer dispersion and a minitablet. A model fluorescent tracer is used to study the ocular release and diffusion from the two dosage forms in humans. To evaluate the prolongation in the cornea/tearfilm compartment, the Apparent Fluorescein TurnOver (%/min) is calculated. The parameters Cmax, tmax, and C9h are used to characterize the pharmacokinetics of Na-fluorescein in the anterior chamber. Furthermore, the swelling behavior of the minitablet is evaluated macroscopically, while the degree of interaction with mucin is characterized by rheological measurements. Calculation of an acceptability score and a slug irritation potential is performed to evaluate user acceptability. In contrast to the hydrated dispersion, the minitablet significantly decreases the Apparent Fluorescein TurnOver (%/min) (P<0.05) and increases the apparent fluorescence in the anterior chamber 9 h after application of the preparation. Rheological data demonstrate the presence of elastic interactions between the polymer and mucin. The dry core of the minitablet becomes fully hydrated after approximately 2 h and is subsequently transformed into a highly concentrated gel. The acceptability of the minitablet is comparable to that of the polymer dispersion. Prolonging the release of Na-fluorescein to the anterior eye segment is only feasible with the dry preparation.

Cold extrusion as a continuous single-step granulation and tabletting process.

The potential of cold extrusion as a continuous granulation/tabletting technique was investigated. Extrudates (X, 9 mm) were produced using twin-screw extrusion, cut manually into tablets (thickness, 4 mm) and dried at 25 degrees C for 20 h. alpha-Lactose monohydrate (200 M) was used as an excipient, PVP (Kollidon K30) and water as binders, and hydrochlorothiazide as the model drug. The influence of formulation (water content, PVP addition, drug incorporation) and process (total input rate and screw speed) parameters on the process (torque, die pressure, visual evaluation of tablets) and on the tablet properties (tensile strength, friability, disintegration time, porosity) was evaluated. Formulation, as well as process parameters, affected the process feasibility, but had only a minor effect on the tablet properties at conditions that allowed continuous tablet production. All alpha-lactose monohydrate tablets formulated without and with PVP and produced at optimum conditions showed tensile strengths above 0.7 and 1.5 MPa, friabilities below 1.0 and 0.9%, and disintegration times below 1 and 8 min, respectively. This technique allows single-step granulation/tabletting of pure alpha-lactose monohydrate, indicating that cold extrusion could be used as alternative tablet production technique for ingredients with poor compaction properties. As the tablets prepared by extrusion have a much higher porosity compared with conventional tablets, this technique could also be useful for tablet production of formulations with poor disintegrating properties.

Stability and compatibility of morphine.

Morphine is a widely used analgesic for the treatment of severe cancer pain. For a large number of terminally ill patients oral administration is no longer possible and morphine is administered parenterally using portable pumps allowing comfortable treatment of the patient at home. In this situation the storage of pre-filled reservoirs and/or the administration over a longer period of time are daily practices and require data on the stability of morphine solutions. As most of these patients suffer from several other symptoms, the administration of admixtures with other drugs is common and requires information on the compatibility of morphine. Morphine degrades in aqueous solutions with the formation of mainly pseudomorphine, to a lesser extent morphine-N-oxide and probably apomorphine. From the study of the kinetics of morphine degradation it was concluded that the degradation of morphine is accelerated in the presence of oxygen and at higher pH of the solution, whereas temperature and light have only a minor influence on the degradation rate. The data reported on the stability of morphine infusion solutions kept under ambient conditions indicated that oxygen, light, the type of reservoir, the type of diluent, the salt form and the concentration of morphine do not affect the stability of morphine solutions stored for up to 3 months. Morphine solutions should preferably be stored at room temperature in order to avoid precipitation at low temperatures and water evaporation at higher temperatures causing increase in morphine concentration when stored in polymer reservoirs. Analyzing the data available on the compatibility of morphine infusion solutions revealed that differences in the formulation of the drug solutions (drug concentration, salt form, type and concentration of additives) and diluent, as well as temperature and order and ratio of mixing might affect the compatibility. Only few reports provide all necessary information, limiting the information useful for daily practice. Moreover, the majority of the compatibility studies are performed in intensive care units, where other drugs and other concentrations of morphine are required than in palliative care settings, limiting its merit for this sector.

Compatibility and stability of ternary admixtures of morphine with haloperidol or midazolam and dexamethasone or methylprednisolone.

The concentration range over which compatible admixtures of morphine hydrochloride with haloperidol lactate (Haldol) or midazolam hydrochloride (Dormicum) and dexamethasone-21-sodium phosphate (Decadron and Decadron Pack) or methylprednisolone-21-sodium succinate (Solu-Medrol) can be prepared was determined by visual evaluation of the solutions at 22 degrees C. The compatibility was evaluated for admixtures prepared in a ratio morphine hydrochloride (D1)/drug 2 (D2)/drug 2 (D3) in a ratio 10/1/1 to 10/1/10 (v/v/v). The solutions of morphine hydrochloride used were 10, 20, 30, 40 and 50 mg/ml prepared in water and isotonized with sodium chloride or dextrose. The drug solutions were used undiluted and diluted 1/5 (v/v) in water. All admixtures were prepared by adding the corticosteroid as D2 and as D3 in order to evaluate the influence of the order of mixing on the compatibility. The stability of the drugs in the compatible admixtures was evaluated during storage for 28 days at 22 degrees C and protected from light. Visual inspection, high performance liquid chromatography (HPLC) analysis, pH and osmolality determinations were performed. For each drug combination incompatibility was observed with increasing ratio and/or concentration of the drug solutions. Within the range of compatibility the concentrations of the three drugs could be increased so to allow adequate symptom control with all drug combinations. For a similar admixture a higher concentrations of corticosteroid could be obtained using dexamethasone-21-sodium phosphate versus methylprednisolone-21-sodium succinate and a higher concentration of dexamethasone-21-sodium phosphate could be obtained without incompatibility using Decadron Pack versus Decadron. The admixtures for which the stability was evaluated were stable for 28 days (> 95% of the initial concentration). None of these admixtures showed any visual changes during storage, except for some of the admixtures prepared using undiluted Decadron, in which small crystals were seen after 1-28 days. The initial pH of the admixture ranged from 3.99 to 6.06 and varied less than 0.10 during storage. The initial osmolality of the admixtures ranged from 170 to 323 mOsm/kg and remained almost constant during storage.

Evaluation of the emulsifying properties of some cationic starches.

Different cationic potato, maize, and waxy maize starches were evaluated for their emulsifying properties. Emulsions were prepared using 20% (w/w) arachidic oil and 80% (w/w) water. Emulsions with the cationic starches as emulsifier in a concentration ranging from 1% to 5% (w/w) were prepared and characterized by droplet size and viscosity measurements, and the stability was evaluated visually and by electrical conductance measurements. None of the cationic potato, waxy maize starches, and maize starches with a low degree of substitution (DS) showed adequate emulsifying properties. Emulsions prepared using non-pregelatinized (C [symbol: see text] bond 05914, 2% and 5% w/w; C [symbol: see text] bond 05907, 5% w/w) and pregelatinized (C [symbol: see text] bond 12504, 5% w/w) cationic maize starches with high-DS were visually stable. The initial mean droplet volume diameter of the emulsions prepared with these cationic starches in a 5% (w/w) concentration was similar and ranged from 2.40 to 2.84 microns; however, there was an important difference in droplet size distribution. The droplet size distribution of the emulsions prepared using the non-pregelatinized high-DS cationic starches was markedly narrower than in the case of the emulsions prepared using the pregelatinized high-DS cationic starches. The droplet size of the emulsions remained almost constant during 120 days of storage. Visual inspection and electrical conductance measurements showed that these emulsions were stable for at least 120 days.

Variability of morphine disposition during long-term subcutaneous infusion in terminally ill cancer patients.

OBJECTIVE: To study the plasma concentrations of morphine and its glucuronides to assess the intra- and interindividual variability of the disposition of morphine administered by subcutaneous infusion in cancer patients. METHODS: Blood samples were taken repeatedly in eight patients with severe cancer pain who were being treated with morphine (60-3000 mg per day) via chronic (8-160 days) subcutaneous infusion. Venous blood samples were collected at least weekly and, when possible, on 3 consecutive days after dose adaptation or any other major change in the patients' treatment. Concentrations of morphine and its glucuronides in plasma were measured after solid-phase extraction using a validated high-performance liquid chromatography assay. The stability of the morphine solutions was determined by repeated measurement of the concentrations of morphine and its degradation products in the solutions. RESULTS: The morphine concentration in the infusion solutions remained unchanged during storage and infusion. The plasma concentrations of morphine and its glucuronides were within the ranges reported in the literature. There was, as expected, a large interindividual variability: from patient to patient, the mean of the normalised plasma concentrations ranged from 0.3 ng.ml(-1).mg(-1) to 0.8 ng.ml(-1).mg(-1) for morphine, from 1.0 ng.ml(-1).mg(-1) to 3.1 ng.ml(-1).mg(-1) for morphine-6-glucuronide and from 6.8 ng.ml(-1).mg(-1) to 24.3 ng.ml(-1).mg(-1) for morphine-3-glucuronide. Intraindividual variability was also important. The residual standard deviation of the mean normalised plasma concentrations calculated for each patient ranged from 26% to 56% for morphine, from 20% to 51% for morphine-6-glucuronide and from 20% to 49% for morphine-3-glucuronide. The normalised plasma concentrations of morphine and its glucuronides did not increase with dose or time, and no explanation for the pronounced pharmacokinetic intraindividual variability was found. CONCLUSION: During subcutaneous infusion of morphine, there is a large intra- and interindividual variability of the morphine disposition which could be of clinical relevance.

Sucrose laurate gels as a percutaneous delivery system for oestradiol in rabbits.

In this study sucrose laurate was formulated in hydrogels and investigated as a suitable transdermal penetration enhancer for oestradiol. Using rabbits as an animal model, the absolute bioavailability and the skin irritation were evaluated after single and multiple application. Three hydrogels containing 60 mg% oestradiol were evaluated: Oestrogel, and two hypromellose gels containing 5 and 15% sucrose laurate (w/w), respectively. No stability problem of the sucrose laurate was detected during a storage period of four months at 7 +/- 2 degrees C. After single application no significant difference (P < 0.05) was observed between the bioavailability parameters of Oestrogel and the 5% sucrose laurate gel. The values obtained for the 15% sucrose laurate gel were significantly higher than for the other gels. When applied on day 7 after a 6-day treatment, twice daily with the respective placebo gel, no significant difference was seen amongst the three formulations for any of the parameters evaluated. When the results after multiple application were compared with those after single application, a significant increase in oestradiol bioavailability was seen for the gel containing 30% ethanol and a significant decrease in oestradiol bioavailability was seen for the 5 and 15% sucrose laurate gels. Histological evaluation of the untreated and treated skin biopsies, showed a significantly higher incidence of infiltrate for all treated skin biopsies in comparison with the untreated ones. A significant increase in skinfold thickness was seen for the skin biopsies treated with gel containing 15% sucrose laurate. It can be concluded that sucrose laurate shows a potential as an absorption enhancer for percutaneous drug delivery.